PubMed

Imeta. 2024 Dec 15;3(6):e251. doi: 10.1002/imt2.251. eCollection 2024 Dec.ABSTRACTThe iMeta Conference 2024 provides a platform to promote the development of an innovative scientific research ecosystem for microbiome and One Health. The four key components - Technology, Research (Biology), Academic journals, and Social media - form a synergistic ecosystem. Advanced technologies drive biological research, which generates novel insights that are disseminated through academic journals. Social media plays a crucial role in engaging the public and facilitating scientific communication, thus amplifying the impact of research. Together, these elements create a self-sustaining loop that fosters continuous innovation and collaboration in the field of bioinformatics, biotechnology and microbiome research.PMID:39742310 | PMC:PMC11683455 | DOI:10.1002/imt2.251

Imeta. 2024 Nov 6;3(6):e246. doi: 10.1002/imt2.246. eCollection 2024 Dec.ABSTRACTFirst introduced in 2021, MetOrigin has quickly established itself as a powerful web server to distinguish microbial metabolites and identify the bacteria responsible for specific metabolic processes. Building on the growing understanding of the interplay between the microbiome and metabolome, and in response to user feedback, MetOrigin has undergone a significant upgrade to version 2.0. This enhanced version incorporates three new modules: (1) Quick search module that facilitates the rapid identification of bacteria associated with a particular metabolite; (2) Orthology analysis module that links metabolic enzyme genes with their corresponding bacteria; (3) Mediation analysis module that investigates potential causal relationships among bacteria, metabolites, and phenotypes, highlighting the mediating role of metabolites. Additionally, the backend MetOrigin database has been updated with the latest data from seven public databases (KEGG, HMDB, BIGG, ChEBI, FoodDB, Drugbank, and T3DB), with expanded coverage of 210,732 metabolites, each linked to its source organism. MetOrigin 2.0 is freely accessible at http://metorigin.met-bioinformatics.cn.PMID:39742299 | PMC:PMC11683456 | DOI:10.1002/imt2.246

Front Nutr. 2024 Dec 17;11:1502151. doi: 10.3389/fnut.2024.1502151. eCollection 2024.ABSTRACTSmall intestinal bacterial overgrowth (SIBO), characterized by alterations in both the type and quantity of bacteria in the small intestine, leads to impaired intestinal digestion and absorption that can cause a range of clinical symptoms. Recent studies have identified significant changes in the composition of the small intestinal microbiota and metabolomic profiles of patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This study systematically reviewed and synthesized the available data to explore the association between SIBO and MASLD. Comprehensive literature searches of the Embase, PubMed, Web of Science, Ovid, and Cochrane databases were conducted. Article quality screening was performed using the Newcastle-Ottawa Quality Assessment Scale. Cross-sectional, cohort, and case-control studies were included. A total of 7,200 articles were initially screened, of which 14 were ultimately included for analysis. Individuals with SIBO in both the MASLD and non-MASLD groups were extracted and a chi-square test was performed to calculate the odds ratio (OR) and 95% confidence interval (CI). The I2 index was used to measure heterogeneity. For heterogeneity >50%, a random effects model was used. There was a clear association between SIBO and MASLD (OR = 3.09; 95% CI 2.09-4.59, I 2 = 66%, p < 0.0001). Subgroup analyses by MASLD stage showed that the probability of SIBO positivity increased with MASLD lesion severity. After stratifying by the diagnostic methods for SIBO and MASLD, the meta-analysis results suggest a reduction in inter-group heterogeneity. For the MASLD subgroup diagnosed via liver biopsy, the OR was 4.89. A subgroup analysis of four studies that included intestinal permeability testing revealed an OR of 3.86 (95% CI: 1.80-8.28, I 2 = 9%, p = 0.0005). A meta-regression analyses revealed that both race and regional development level significantly influenced the relationship between SIBO and MASLD (p = 0.010, p = 0.047). In conclusion, this meta-analyses provides strong evidence that SIBO may contribute to the development and progression of MASLD. The strongest associations were observed between lactulose breath testing, gut microbiota culture, liver biopsy diagnosis of MASLD, and SIBO detected through intestinal permeability testing. The primary sources of heterogeneity are race and developed regions.SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=427040.PMID:39742106 | PMC:PMC11685094 | DOI:10.3389/fnut.2024.1502151

Front Nutr. 2024 Dec 17;11:1536519. doi: 10.3389/fnut.2024.1536519. eCollection 2024.NO ABSTRACTPMID:39742099 | PMC:PMC11685067 | DOI:10.3389/fnut.2024.1536519

Int J Nanomedicine. 2024 Dec 27;19:13949-13971. doi: 10.2147/IJN.S494262. eCollection 2024.ABSTRACTINTRODUCTION: The anti-cancer properties of zinc oxide-doped carbon dots (CDs/ZnO) in inhibiting triple-negative breast cancer (TNBC) progression merit more investigation.METHODS: With citric acid as the carbon source, urea applied as the nitrogen source, and zinc oxide (ZnO) used as a reactive dopant, CDs/ZnO were synthesized by microwave heating in the current study, followed by the characterization and biocompatibility assessments. Subsequently, the anti-cancer capabilities of CDs/ZnO against TNBC progression were evaluated by various biochemical and molecular techniques, including viability, proliferation, migration, invasion, adhesion, clonogenicity, cell cycle distribution, apoptosis, redox homeostasis, metabolome, and transcriptome assays of MDA-MB-231 cells. Additionally, the in vivo anti-cancer potentials of CDs/ZnO against TNBC progression were analyzed using TNBC xenograft mouse models.RESULTS: The biocompatibility of CDs/ZnO was supported by the non-significant changes in the pathological and physiological parameters in the CDs/ZnO treated mice, alongside a non-cytotoxic effect of CDs/ZnO on the proliferation of normal cells. Notably, the CDs/ZnO treatments effectively decreased the viability, proliferation, migration, invasion, adhesion, and clonogenicity of MDA-MB-231 cells. Furthermore, the CDs/ZnO treatments induced cell cycle arrest, apoptosis, redox imbalance, metabolome disturbances, and transcriptomic alterations of MDA-MB-231 cells by regulating the MAPK signaling pathway. Additionally, the CDs/ZnO treatments markedly suppressed the in vivo tumor growth in the TNBC xenograft mouse models.CONCLUSION: In this study, we synthesized CDs/ZnO via microwave heating, using citric acid as the carbon source, urea as the nitrogen source, and ZnO as a reactive dopant. We confirmed the biosafety and potent anti-cancer efficacy of CDs/ZnO in inhibiting TNBC progression by disrupting malignant cell behaviors through modulation of the MAPK signaling pathway.PMID:39742095 | PMC:PMC11687324 | DOI:10.2147/IJN.S494262

Cardiovasc Ther. 2024 Aug 14;2024:7004371. doi: 10.1155/2024/7004371. eCollection 2024.ABSTRACTDetection of biomarkers was extremely important for the early diagnosis, prognosis, and therapy optimization of diseases. The purpose of this study was to investigate the differences in serum metabolites between patients with heart failure (HF) and healthy control (HC) and to diagnose HF qualitatively. In this study, serum samples from 83 patients with HF and 35 HCs were used as the research subjects for untargeted metabolomic analysis using ultraperformance liquid chromatography combined with quadrupole-time of flight mass spectrometry (UPLC-QTOF/MS) technology. Potential biomarkers were screened and validated using the orthogonal partial least squares discriminant analysis (OPLS-DA), random forest (RF), binary logistic regression (BLR), and receiver operating characteristic (ROC) analysis. The results indicated that a total of 43 metabolites were considered as differentially expressed metabolites (DEMs). Among these DEMs, glycodeoxycholate was identified as a specific biomarker of HF. A ROC curve analysis for HC versus HF discrimination showed an area under the ROC curve (AUC) of 0.9853 (95% CI: 0.9859-1.0000), a sensitivity of 95%, and a specificity of 100%. Hence, glycodeoxycholate might serve as a potential biomarker for HF. Furthermore, the amino acid metabolism was screened as the most significantly altered pathway in patients with HF. By identifying serum biomarkers and analyzing metabolic pathways, our study provided opportunities to enhance the understanding of the pathogenesis and early diagnosis of HF.PMID:39742011 | PMC:PMC11338663 | DOI:10.1155/2024/7004371

Cardiovasc Ther. 2024 Aug 30;2024:9935805. doi: 10.1155/2024/9935805. eCollection 2024.ABSTRACTPatients with stable coronary artery disease (CAD) are at an increased risk of acute myocardial infarction (AMI), particularly among older individuals. Developing a reliable model to predict AMI occurrence in these patients holds the potential to expedite early diagnosis and intervention. This study is aimed at establishing a circulating amino acid-assisted model, incorporating amino acid profiles alongside clinical variables, to predict AMI risk. A cohort of 874 CAD patients from two independent centers was analyzed. Plasma amino acid levels were quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS) employing a targeted metabolomics approach. This methodology incorporated 13C isotope-labeled internal standards for precise quantification of 27 amino acids. Univariate logistic regression was applied to identify differentially expressed amino acids that distinguished between stable CAD and AMI patients. To assess prediction performance, receiver operating characteristic (ROC) curve and nomogram analyses were utilized. Five amino acids-lysine, methionine, tryptophan, tyrosine, and N6-trimethyllysine-emerged as potential biomarkers (p < 0.05), exhibiting significant differences in their expression levels across the two centers when comparing stable CAD with AMI patients. For AMI risk prediction, the base model, utilizing 12 clinical variables, achieved areas under the curve (AUC) of 0.7387 in the discovery phase (n = 623) and 0.8205 in the external validation set (n = 251). Notably, the integration of these five amino acids into the prediction model significantly enhanced its performance, increasing the AUC to 0.7651 in the discovery phase (Delong's test, p = 1.43e-02) and to 0.8958 in the validation set (Delong's test, p = 8.91e-03). In conclusion, the circulating amino acid-assisted model effectively enhances the prediction of AMI risk among CAD patients, indicating its potential clinical utility in facilitating early detection and intervention.PMID:39742009 | PMC:PMC11379511 | DOI:10.1155/2024/9935805

Microbiome Res Rep. 2024 Sep 18;3(4):49. doi: 10.20517/mrr.2024.33. eCollection 2024.ABSTRACTAim: Accumulating evidence highlights the crucial role of the "gut-brain axis" and emphasizes the potential of dietary interventions to improve brain health through this pathway. This study assesses the effects of the probiotic Pediococcus acidilactici CCFM6432 on mood, sleep, and gastrointestinal function in patients with depressive disorder. Methods: This clinical trial is a randomized, placebo-controlled study (Registration: ChiCTR2300071025). It enrolled 39 adult patients diagnosed with depressive disorder, who were randomly assigned to either the placebo control group (n = 19) or the CCFM6432 intervention group (n = 20). The intervention period spanned four weeks. Assessments were conducted at both the beginning and end of the trial, including comprehensive questionnaire evaluations and the collection of serum and fecal samples. Results: In comparison to the placebo, treatment with CCFM6432 significantly decreased depression and anxiety scores, as well as ameliorated gastrointestinal dysfunction and poor sleep quality commonly associated with mood disorders. Microbiota analysis revealed an increase in species richness without notable changes in overall diversity, yet Pediococcus species was found to be more abundant post-treatment. Functional analysis indicated reduced activity in the NOD-like receptor signaling pathway, suggesting anti-inflammatory effects induced by the probiotic. Metabolomic profiling identified elevated levels of fecal lactic acid, which correlated with lower Hospital Anxiety and Depression Scale (HADS) scores, thereby linking probiotic metabolism to mood enhancement. Conclusion: These findings imply that CCFM6432 may improve brain function by modulating gut microbiota and their mediated immune homeostasis, underscoring its potential as an adjunctive treatment for mental disorders.PMID:39741947 | PMC:PMC11684983 | DOI:10.20517/mrr.2024.33

Front Mol Biosci. 2024 Dec 17;11:1483326. doi: 10.3389/fmolb.2024.1483326. eCollection 2024.ABSTRACTThyroid diseases, including functional and neoplastic diseases, bring a huge burden to people's health. Therefore, a timely and accurate diagnosis is necessary. Mass spectrometry (MS) based multi-omics has become an effective strategy to reveal the complex biological mechanisms of thyroid diseases. The exponential growth of biomedical data has promoted the applications of machine learning (ML) techniques to address new challenges in biology and clinical research. In this review, we presented the detailed review of applications of ML for MS-based multi-omics in thyroid disease. It is primarily divided into two sections. In the first section, MS-based multi-omics, primarily proteomics and metabolomics, and their applications in clinical diseases are briefly discussed. In the second section, several commonly used unsupervised learning and supervised algorithms, such as principal component analysis, hierarchical clustering, random forest, and support vector machines are addressed, and the integration of ML techniques with MS-based multi-omics data and its application in thyroid disease diagnosis is explored.PMID:39741929 | PMC:PMC11685090 | DOI:10.3389/fmolb.2024.1483326

Front Plant Sci. 2024 Dec 16;15:1515944. doi: 10.3389/fpls.2024.1515944. eCollection 2024.ABSTRACTDrought, a major consequence of climate change, initiates molecular interactions among genes, proteins, and metabolites. Agropyron mongolicum a high-quality perennial grass species, exhibits robust drought resistance. However, the molecular mechanism underlying this resistance remaining largely unexplored. In this study, we performed an integrated analysis of the transcriptome, proteome, and metabolome of A. mongolicum under optimal and drought stress conditions. This combined analysis highlighted the pivotal role of transporters in responding to drought stress. Moreover, metabolite profiling indicated that arginine and proline metabolism, as well as the pentose phosphate pathway, are significantly involved in the drought response of A. mongolicum. Additionally, the integrated analysis suggested that proline metabolism and the pentose phosphate pathway are key elements of the drought resistance strategy in A. mongolicum plants. In summary, our research elucidates the drought adaptation mechanisms of A. mongolicum and identifies potential candidate genes for further study.PMID:39741683 | PMC:PMC11685866 | DOI:10.3389/fpls.2024.1515944

Front Plant Sci. 2024 Dec 17;15:1477605. doi: 10.3389/fpls.2024.1477605. eCollection 2024.ABSTRACTMicroplastics are widely present in the environment and can adversely affect plants. In this paper, the effects of different concentrations of microplastics on physiological indices and metabolites of highland barley were investigated for the first time using a metabolomics approach, and revealed the response mechanism of barley seedlings to polystyrene microplastics (PS-MPs) was revealed. The results showed that the aboveground biomass of highland barley exposed to low (10 mg/L) and medium (50 mg/L) concentrations of PS-MPs increased by 32.2% and 48.2%, respectively. The root length also increased by 16.4% and 21.6%, respectively. However, the aboveground biomass of highland barley exposed to high (100 mg/L) concentrations of PS-MPs decreased by 34.8%, leaf length by 20.7%, and root length by 25.9%. Microplastic exposure increased the levels of antioxidant activity, suggesting that highland barley responds to microplastic stress through oxidative stress. Metabolome analysis revealed that the contents of 4 metabolites increased significantly with increasing PS-MPs concentration in positive ionmode, while the contents of 8 metabolites increased significantly with increasing PS-MPs concentration in negative ionmode (P < 0.05), including prunin, dactylorhin E, and schisantherin B. Additionally, PS-MPs significantly interfered with highland barley flavonoid biosynthesis, pyrimidine metabolism, purine metabolism, fatty acid biosynthesis, and phenylpropanoid biosynthesis metabolic pathways. This study provides a new theoretical basis for a deeper understanding of the effects of different concentrations of PS-MPs on highland barley.PMID:39741681 | PMC:PMC11685026 | DOI:10.3389/fpls.2024.1477605

Front Plant Sci. 2024 Dec 17;15:1464747. doi: 10.3389/fpls.2024.1464747. eCollection 2024.ABSTRACTAlfalfa (Medicago sativa L.), a prominent perennial forage in the legume family, is widely cultivated across Europe and America. Given its substantial economic value for livestock, breeding efforts have focused on developing high-yield and high-quality varieties since the discovery of CMS lines. However, progress is restricted by the limitations of existing CMS lines, necessitating the development of new lines and study of the molecular mechanisms underlying pollen abortion. This study investigates early-stage anther development in cytoplasmic male sterile (CMS) alfalfa lines (MSJN1A) in relation to the isotypic maintainer line (MSJN1B). Histological analyses revealed abnormal degradation of tapetal cells post-meiosis in the CMS line. Notably, during the early mononuclear stage, the central vacuoles in the microspores were absent, leading to evident pollen abortion. These findings suggest that pollen abortion in the CMS line is associated with the delayed disintegration of the tapetum and structural anomalies in microspore vacuoles. Non-targeted metabolome sequencing revealed 401 and 405 metabolites at late tetrad and early mononuclear stages of alfalfa, respectively. Among these, 39 metabolites were consistently upregulated, whereas 85 metabolites were downregulated. Differential analysis revealed 45 and 37 unique metabolites at each respective stage. These metabolites were primarily featured in pathways related to energy, phenylpropane, sucrose and starch, and fatty acid metabolism. Integrated analysis demonstrated that differentially expressed genes and differential metabolites were co-enriched in these pathways. Additionally, quantitative real-time PCR and physiological index analysis confirmed downregulation of key genes involved in anther development, illustrating that changes in upstream gene regulation could significantly impact downstream metabolite levels, ultimately influencing pollen fertility. Pollen abortion is related to abnormal phenylpropane metabolism, fatty acid metabolism and starch and sucrose pathway, which provides reference for further research on the causes of pollen abortion of alfalfa.PMID:39741675 | PMC:PMC11687225 | DOI:10.3389/fpls.2024.1464747

J Transl Med. 2024 Dec 31;22(1):1163. doi: 10.1186/s12967-024-06011-y.ABSTRACTBACKGROUND: As a prevalent and deadly malignant tumor, the treatment outcomes for late-stage patients with cervical squamous cell carcinoma (CSCC) are often suboptimal. Previous studies have shown that tumor progression is closely related with tumor metabolism and microenvironment reshaping, with disruptions in energy metabolism playing a critical role in this process. To delve deeper into the understanding of CSCC development, our research focused on analyzing the tumor microenvironment and metabolic characteristics across different regions of tumor tissue.METHODS: Utilizing spatial transcriptomics (ST) sequencing technology, we conducted a study on FFPE (formalin-fixed paraffin-embedded) tumor samples from CSCC patients. Coupled with single-cell RNA sequencing (scRNA-seq) data after deconvolution, we described spatial distribution maps of tumor leading edge and core regions in detail. Tumor tissues were classified into hypermetabolic and hypometabolic regions to analyze the metabolism profiles and tumor differentiation degree across different spatial areas. We also employed The Cancer Genome Atlas (TCGA) database to examine the analysis results of ST data.RESULTS: Our findings indicated a more complex tumor microenvironment in hypermetabolic regions. Cell-cell communication analysis showed that various cells in tumor microenvironment were influenced by the signalling molecule APP released by cancer cells and higher expression of APP was observed in hypermetabolic regions. Furthermore, our results revealed the correlation between APP and the transcription factor TRPS1. Both APP and TRPS1 demonstrated significant effects on cancer cell proliferation, migration, and invasion, potentially contributing to tumor progression.CONCLUSIONS: Utilizing ST, scRNA-seq, and TCGA database, we examined the spatial metabolic profiles of CSCC tissues, including metabolism distribution, metabolic variations, and the relationship between metabolism and tumor differentiation degree. Additionally, potential cancer-promoting factors were proposed, offering a valuable foundation for the development of more effective treatment strategies for CSCC.PMID:39741285 | DOI:10.1186/s12967-024-06011-y

Biol Direct. 2024 Dec 31;19(1):147. doi: 10.1186/s13062-024-00574-y.ABSTRACTBACKGROUND: Integrating multi-layered information can enhance the accuracy of genomic prediction for complex traits. However, the improvement and application of effective strategies for genomic prediction (GP) using multi-omics data remains challenging.METHODS: We generated 11 feature sets for sequencing variants from genomics, transcriptomics, metabolomics, and epigenetics data in beef cattle, then we assessed the contribution of functional variants using genomic restricted maximum likelihood (GREML). We next estimated and ranked variant scores for 43 economically important traits, and compared the prediction accuracy of the top and bottom sets using genomic best linear unbiased prediction (GBLUP) and BayesB model. In addition, we annotated the variants from GWAS with functional feature sets and performed enrichment analysis.RESULTS: We observed significant enrichments for 32 functional categories in 11 feature sets. The evolutionary related sets (conservation regions and selection signatures) contributed significantly to heritability (31.78-fold and 14.48-fold enrichment), while metabolomics and transcriptomics showed low heritability enrichments. We observed a significant increase in prediction accuracy using the top feature set variants compared to whole-genome sequencing (WGS) data. The prediction accuracy based on the top 10% variant set showed an average increase of 11.6% and 7.54% using BayesB and GBLUP across traits, respectively. Notably, the greatest increase of 31.52% was obtained for spleen weight (SW) using BayesB. Also, we found that the top 10% of variants show strong enrichment with weight related QTLs based on the Cattle QTL database.CONCLUSIONS: Our findings suggest that integrating biological prior information from multiple layers can enhance our understanding of the genetic architecture underlying complex traits and further improve genomic prediction in beef cattle.PMID:39741345 | DOI:10.1186/s13062-024-00574-y

J Transl Med. 2024 Dec 31;22(1):1165. doi: 10.1186/s12967-024-05973-3.ABSTRACTBACKGROUND: Autism spectrum disorder (ASD) is a persistent neurodevelopmental disorder affecting brains of children. Mounting evidences support the associations between gut microbial dysbiosis and ASD, whereas detailed mechanisms are still obscure.METHODS: Here we probed the potential roles of gut microbiome in ASD using fecal metagenomics and metabolomics.RESULTS: Children with ASD were found to be associated with augmented serum cytokines milieu, especially TNFα. Metagenomic analysis generated 29 differential species and 18 dysregulated functional pathways such as Bifidobacterium bifidum, Segatella copri, and upregulated 'Sphingolipid metabolism' in children with ASD. Metabolomics revealed steroid hormone dysgenesis in children with ASD with lower abundances of metabolites such as estriol, estradiol and deoxycorticosterone. A three-way association analysis showed positive correlations between TNFα and microbial function potentials such as 'Bacterial toxins' and 'Lysosome', indicating the contribution of microbial dysbiosis to neuroinflammation. TNFα also correlated positively with 'Sphingolipid metabolism', which further showed negative correlations with metabolites estriol and deoxycorticosterone. Such results, in consistent with current findings, revealed the contribution of increased TNFα to upregulated sphingolipid metabolism, which further impaired steroid hormone biosynthesis.CONCLUSION: Our study proposed the gut microbial 'TNFα-sphingolipids-steroid hormones' axis in children with ASD, which may provide new perspectives for developing gut microbiome-based treatments in the future.PMID:39741321 | DOI:10.1186/s12967-024-05973-3

J Transl Med. 2024 Dec 31;22(1):1164. doi: 10.1186/s12967-024-05970-6.ABSTRACTBACKGROUND: Pancreatic cancer (PC) is a lethal malignancy characterized by poor prognosis and high mortality. We found the highly expressed RNA-binding motif protein 47 (RBM47) in PC progression. The RBM47 expression was negatively correlated with natural killer (NK) cell infiltrate in PC. Moreover, RBM47 was predicted to bind to the 3'-UTR region of Protein Disulfide Isomerase Family A Member 6 (PDIA6), an oncogene of the development of PC. Therefore, we supposed that RBM47 might affect PC progression by regulating PDIA6.METHODS: Bioinformatics analysis was performed to screen the candidate gene affecting PC progression using public databases. Loss- and gain-of-function effects of RBM47 on cell proliferation, tumor growth, and immune evasion were determined by CCK-8, EdU incorporation, colony formation assays, the xenogeneic tumor model, and co-culture system of PC and NK-92 cells. RBM47-RNA immunoprecipitation (RIP) followed by PCR and dual luciferase reporter assay were used to detect whether RBM47 could interact with the PDIA6 mRNA and how RBM47 would regulate the transcriptional activity of PDIA6, respectively. Simultaneous overexpression of PDIA6 in RBM47 knockdown PC cells was conducted to clarify whether PDIA6 would mediated effects of RBM47. Given the important role of cellular metabolism in cells proliferation and immune evasion, PC cells with RBM47 knockdown were subjected to metabolomics analysis to further investigate how RBM47 regulate PC progression.RESULTS: RBM47 overexpression drove PC progression by promoting cell proliferation and xenografted tumor growth. Consistently, our results showed that RBM47 overexpression weakened sensitivity of PC cells to cytotoxic NK cells. However, RBM47 knockdown exhibited the opposite effects on proliferation and immune evasion of PC cells. RBM47 was able to bind to the 3'-UTR region of PDIA6, maintained PDIA6 mRNA stability, and increased the PDIA6 expression in PC cells. Rescue experiments supported that PDIA6 overexpression reversed the suppressing effects of RBM47 knockdown on cell proliferation and immune evasion. RBM47 knockdown significantly changed metabolites of PC cells.CONCLUSIONS: In summary, our findings demonstrate that RBM47 contributes to PC progression, which might be mediated by the upregulated PDIA6 expression and the altered cellular metabolites in PC cells, offering a potential therapeutic target for PC treatment.PMID:39741300 | DOI:10.1186/s12967-024-05970-6

BMC Complement Med Ther. 2024 Dec 31;24(1):429. doi: 10.1186/s12906-024-04725-6.ABSTRACTBACKGROUND: The treatment of advanced colorectal cancer (CRC) has progressed slowly, with chemotherapy combined with targeted therapy being the first-line treatment for the disease, but the improvement in efficacy is not satisfactory. Compound Kushen injection (CKI) is one of the representative drugs of anti-cancer Chinese herbal injection drugs, which has been widely used in the adjunct treatment of cancer in China. The aim of this trial is to evaluate the efficacy and safety of CKI combined with first-line treatment of advanced CRC.METHODS: This is a multicenter, randomized, open-label controlled clinical trial in which 320 patients with advanced CRC will be randomly assigned to the treatment group or the control group in a 1:1 ratio. Both groups will receive at least 4 cycles of first-line therapy (FOLFOX/FOLFIRI/CAPEOX ± cetuximab/bevacizumab) in 14-21 day cycles, and the experimental group will receive additional CKI with a cumulative dose of 200 ml per cycle. Patients who achieve a complete response, partial response, or stable disease after 4-6 months will receive maintenance therapy until disease progression or another endpoint event, such as toxicity or death, occurs.. Follow-up will occur every 3 months until death or loss to follow-up. The primary outcome of this study will be progression-free survival (PFS). Secondary outcomes will be overall survival (OS), 1-year OS rate, 1-year PFS rate, objective response rate,disease control rate, symptoms and quality of life evaluation. Safety outcomes will be incidence of adverse events.DISCUSSION: This study will be the first randomized controlled trial to investigate the efficacy and safety of CKI when combined with first-line treatment in the treatment of advanced CRC, with PFS as the primary outcome. It aims to clarify the clinical advantages and therapeutic effect of CKI in the treatment of advanced CRC. To identify the benefit population of CKI in the treatment of patients with advanced CRC, an enrichment design based on biomarkers will be utilized. Metabolomics and gut microbiota analysis will be conducted on biological samples to explore the metabolic and gut microbiota differences associated with the efficacy of CKI, guiding further research into its mechanism of action.TRIAL REGISTRATION: ClinicalTrials.govNCT05894694. Registered on 4 August 2023.PMID:39741233 | DOI:10.1186/s12906-024-04725-6

Angew Chem Int Ed Engl. 2024 Dec 30:e202420149. doi: 10.1002/anie.202420149. Online ahead of print.ABSTRACTCholine kinase alpha (CHKA) is a central mediator of cell metabolism linked to cancer and immune regulation. Cellular and clinical evaluation of CHKA has been hampered by challenges in the development of drug-like choline kinase inhibitors. Here, we identify CHKA as an unexpected off-target of histone methyltransferase inhibitors using an integrated phenomic approach. We confirm CHKA as a direct protein target of the aminoquinazolines UNC0638 and UNC0737 using a combination of chemoproteomic, biochemical, cellular, and metabolic profiling assays, possibly explaining the previously reported discrepancies observed for different G9a/GLP inhibitor scaffolds in cellular assays. Using primary human cell model systems, we discover that CHKA modulation impairs IgG secretion and B-cell maturation consistent with the notion that choline metabolism plays an important role in immune signalling. Co-crystal structures of UNC0638 and UNC0737 with CHKA unravel an unexpected binding mode and suggest the inhibitors as attractive starting points for the development of selective chemical tools to further explore the biological role of CHKA in cancer and immune metabolism.PMID:39740997 | DOI:10.1002/anie.202420149

BMJ Open. 2024 Dec 31;14(12):e092902. doi: 10.1136/bmjopen-2024-092902.ABSTRACTINTRODUCTION: Previous randomised controlled trials (RCTs) have indicated a protective role of pregnancy supplementation with fish oil and high-dose vitamin D, respectively, on offspring asthma, infections and several other disorders in early childhood. However, current evidence is not considered sufficient for recommending these supplements in pregnancy. In two RCTs, we aim to investigate whether these protective effects can be confirmed in larger trials with the goal of changing clinical practice and improving child health.METHODS AND ANALYSIS: Randomisation of 4000 pregnant women to either (1) (n=2000) the fish oil trial of 2.4 g/day (55% eicosapentaenoic acid (EPA) and 37% docosahexaenoic acid (DHA)) in triacylglycerol form versus placebo or (2) (n=2000) the vitamin D trial of high-dose (3200 IU/day) vitamin D versus placebo on top of the recommended 400 IU/day. Supplementation begins in gestational week 24 (22-26) until 1 week after delivery. Allocation to the trials will be determined based on the preinterventional maternal blood levels of EPA+DHA with a dried blood screening test. Women with low levels (below 4.7% of total fatty acids) will be assigned to the fish oil RCT, and women with high levels will be assigned to the vitamin D RCT. Maternal blood will be used for genetic, metabolomic and proteomic profiling. A 3-year follow-up of the children with longitudinal registration of parent-reported symptoms, diagnoses, medication use and hospitalisations will be performed. The primary outcome is persistent wheeze or asthma until age 3 years, with predefined analyses of effect modification by maternal genotypes. Secondary outcomes are lower respiratory tract infections, gastrointestinal infections, croup, troublesome lung symptoms, eczema, allergy, bone fractures, developmental milestones, mental health, cognition and growth until age 3 years. A follow-up on both primary and secondary outcomes is planned after unblinding, from age 3-6 years.ETHICS AND DISSEMINATION: The RCTs are approved by the Danish local ethics committee (H-23055833). The studies are registered at ClinicalTrials.gov (NCT06560255 and NCT06570889). Study results will be communicated to the medical community, including publications in peer-reviewed journals. All results will be published and available on www.copsac.com.TRIAL REGISTRATION NUMBER: NCT06560255 and NCT06570889.PMID:39740942 | DOI:10.1136/bmjopen-2024-092902

NanoImpact. 2024 Dec 29:100537. doi: 10.1016/j.impact.2024.100537. Online ahead of print.ABSTRACTThe persistent detection of nano-sized plastic particles in humans, animals, and animal-derived products underscores the potential impact of these particles on living organisms. Consequently, the toxicology of such particles has emerged as a pivotal research interests in recent years. In this study, NP was synthesized successfully with an average particle size of 100 nm using a emulsion polymerization method as model particles. Following co-incubation of IEC-6 cells with NP for 24-168 h, a notable inhibition of cell viability and proliferation was observed. The significant activation of autophagy and a concomitant blockage of autophagic flux in IEC-6 cells after 24-72 h of co-incubation with NP were unveiled by transmission electron microscopy, western blotting, and double-fluorescent autophagy analysis. A significant increase in the number of lysosomes and an increase in the expression of hydrolase CTSB were detected, indicating dysregulation of lysosomal function. The subsequent transcriptomic and metabolomics analyses, coupled with the observation of activated lysosomes and the RIPK1-RIPK3-MLKL/PYGL pathway, led us to posit that the blockade of autophagy and lysosomal dysfunction, culminating in lysosomal membrane permeabilization (LMP) induced necroptosis, constitutes one of the mechanisms contributing to the cytotoxicity of NP. SYNOPSIS: The cytotoxicity and its related mechanisms of nano-plastic is still unclear. This study found that nano-plastics may induce necroptosis in cells, and autophagy blockade and lysosomal dysfunction are prodromal manifestations.PMID:39740740 | DOI:10.1016/j.impact.2024.100537